Drug addiction arising from abuse of cocaine and other psychomotor stimulants continues to be a critical public health concern. Currently, effective pharmacotherapies are not available to combat the addictive power of cocaine. Consequently, medication strategies and candidate medications that reduce cocaine's reinforcing strength need to be identified. The proposed research is designed to address these problems with innovative self-administration procedures in which dose-effect functions for the relative reinforcing strength of cocaine can be rapidly determined. Self-administration procedures in nonhuman primates have been integral to previous studies of abuse liability and drug dependence; however, procedures that are suitably modified to identify medications that alter reinforcing strength, particularly in chronic studies and under varying behavioral conditions, have not yet been advanced. In our novel procedure, rhesus monkeys learn to distribute their behavior throughout the session on the basis of the relative reinforcing strengths of an i.v. solution that is available for self-injection and an alternative reinforcer (food). This procedure is especially designed to divorce the reinforcing strength of drugs from their other behavioral effects. In proposed studies, the distribution of behavior will be determined under varying conditions of response cost and response suppression to establish the full range of cocaine's relative reinforcing strength. Next, the acute and chronic effects of drugs that represent different agonist-based medication strategies will be fully evaluated. Strategies will be based upon indirect and direct monoaminergic mechanisms that may be associated with the reinforcing or other subjective effects of stimulant drugs. It is expected that some strategies may more effectively combat the reinforcing strength of cocaine when it is low whereas other strategies may be useful over a wider range of conditions. The effects of selected drugs in combination also will be evaluated to explore the possibility that mechanistic synergism may expand the effectiveness or increase the potency of medications. Finally, the effects of candidate medications on cocaine's overt behavioral effects (visual scanning/checking) also will be evaluated during chronic exposure. These effects may be related to behavioral toxicity, and will provide important information with which to evaluate the therapeutic advantage of different agonist-based medication strategies. Overall, our proposed studies in monkeys will provide significant advances for evaluating the reinforcing strength of cocaine and for assessing the effectiveness with which different agonist-based medications may combat the addictive power of stimulant drugs.